Antigenic mapping of emerging SARS-CoV-2 omicron variants BM.1.1.1, BQ.1.1, and XBB.1
Authors: Anna Z Mykytyn, Miruna E Rosu, Adinda Kok, Melanie Rissmann, Geert van Amerongen, Corine Geurtsvankessel, Rory D de Vries, Bas B Oude Munnink, Derek J Smith, Marion P G Koopmans, Mart M Lamers, Ron A M Fouchier, Bart L Haagmans
Journal: The Lancet Microbe (2023)

Novel SARS-CoV-2 omicron variants, including BM.1.1.1, BQ.1.1, and XBB.1, continue to emerge at an unprecedented rate, evading pre-existing immunity from vaccination and previous infection. Quantifying the antigenic diversity of variants might assist in selecting future vaccine strains. To determine the antigenic relationships between emerging SARS-CoV-2 omicron variants, we and others1Wilks SH Mühlemann B Shen X et al.Mapping SARS-CoV-2 antigenic relationships and serological responses.bioRxiv. 2022; (published online July 13.) (preprint).https://doi.org/10.1101/2022.01.28.477987PubMed Google Scholar, 2Wang W Lusvarghi S Subramanian R et al.Antigenic cartography of well-characterized human sera shows SARS-CoV-2 neutralization differences based on infection and vaccination history.Cell Host Microbe. 2022; 30: 1745-1758Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 3van der Straten K Guerra D van Gils MJ et al.Antigenic cartography using sera from sequence-confirmed SARS-CoV-2 variants of concern infections reveals antigenic divergence of omicron.Immunity. 2022; 55: 1725-1731Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 4Mykytyn AZ Rissmann M Kok A et al.Antigenic cartography of SARS-CoV-2 reveals that omicron BA.1 and BA.2 are antigenically distinct.Sci Immunol. 2022; 7eabq4450Crossref Scopus (16) Google Scholar used antigenic cartography, whereby multidimensional scaling is used to generate antigenic maps in which the positions of antigens and antiserum samples directly correspond to neutralising titres. This method allows for the quantification and visualisation of antigenic properties of different variants simultaneously. Previously, we used the hamster model for SARS-CoV-2 to generate an antigenic map.4Mykytyn AZ Rissmann M Kok A et al.Antigenic cartography of SARS-CoV-2 reveals that omicron BA.1 and BA.2 are antigenically distinct.Sci Immunol. 2022; 7eabq4450Crossref Scopus (16) Google Scholar We now inoculated hamsters with the currently dominant omicron BA.5 variant, which is genetically close to BA.2, differing in the spike amino acid sequence by only three substitutions and two deletions (appendix p 1). Neutralising titres were determined using all serum samples and variants grown previously, along with omicron BA.5 and the omicron BQ.1.1, BM.1.1.1, and XBB.1 variants, which emerged in late 2022 (appendix p 2). Omicron BA.5 antiserum samples neutralised the homologous virus, BA.2, and BQ.1.1 efficiently, whereas omicron BM.1.1.1 was poorly neutralised. None of the serum samples were able to substantially neutralise XBB.1. Next, we generated an updated antigenic map using all available antiserum samples and viral variants (appendix p 3). In this map, all omicron variants were positioned distantly from the pre-omicron cluster. Omicron BA.5 was positioned within one antigenic unit from BA.2, with an antigenic unit representing a two-fold dilution in neutralisation titrations. All remaining omicron variants were positioned 2·3 to 7·0 antigenic units from each other. Omicron BQ.1.1, BM.1.1.1, and XBB.1 mapped the furthest from the pre-omicron variants. Similar results were observed in a map generated in three dimensions (appendix p 4). The data were well represented in two and three dimensions, with no substantial improvement at a higher number of dimensions (appendix p 5). Two dimensional and three dimensional map distances correlated well with neutralisation titres and overall there was good coordination and accuracy in the placement of the antigens and serum samples. Despite the lower certainty in the positioning of BQ.1.1, BM.1.1.1, and XBB.1, the reactive heterologous serum samples present in the map, which are well spaced, allow for a good approximation of the antigenic position of new variants (without their respective homologous serum samples). We observed that human post-vaccination neutralisation titres reflected the antigenic map, as the largest reduction in neutralising titres compared with the D614G variant is against omicron BQ.1.1, BM.1.1.1, and XBB.1, followed by omicron BA.1, BA.2, and BA.5 to similar levels (appendix p 6). Our data reveal substantial cross-neutralisation of BA.5 antiserum samples against BQ.1.1 but little cross-neutralisation against XBB.1 and BM.1.1.1. Despite the antigenic similarities between BA.5 and BQ.1.1, thus far there is little evidence for increased neutralisation of BQ.1.1 by BA.5 bivalent vaccines, potentially due to immunological imprinting.5Zou J Kurhade C Patel S et al.Improved Neutralization of omicron BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with bivalent BA.4/5 vaccine.bioRxiv. 2022; (published online Nov 17.) (preprint).https://doi.org/10.1101/2022.11.17.516898Google Scholar, 6Kurhade C Zou J Xia H et al.Low neutralization of SARS-CoV-2 omicron BA.2.75·2, BQ.1.1, and XBB.1 by parental mRNA vaccine or a BA.5-bivalent booster.Nat Med. 2022; (published online Dec 6.)https://doi.org/10.1038/s41591-022-02162-xCrossref PubMed Scopus (7) Google Scholar, 7Park YJ Pinto D Walls AC et al.Imprinted antibody responses against SARS-CoV-2 omicron sublineages.Science. 2022; 378: 619-627Crossref PubMed Scopus (6) Google Scholar In addition, these newly emerging variants do not cluster close to each other, therefore a vaccine based on any of these variants might poorly cross-neutralise new, emerging variants, which could be equally antigenically distant. Continuous mapping of new variants and a greater understanding of the evolutionary trajectory of SARS-CoV-2 could indicate potential vaccine candidates. This online publication has been corrected. The corrected version first appeared at thelancet.com/microbe on February 7, 2023 This online publication has been corrected. The corrected version first appeared at thelancet.com/microbe on February 7, 2023 This work was financially supported by the Health∼Holland grant LSHM19136 to BLH; cofunded by the PPP Allowance made available by the Health∼Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships, and the European Union's Horizon 2020 research and innovation program under grant number 101003589 (RECoVER; to MPGK) and EU funding grant agreement number 874735(VEO). BLH, RAMF, DJS, and MPGK are supported by the NIH/NIAID Centers of Excellence for Influenza Research and Response under contract 75N93021C00014-Icahn School of Medicine at Mt Sinai. MER and AK contributed equally. Download .pdf (5.09 MB) Help with pdf files Supplementary appendix Correction to Lancet Microbe 2023; published online Jan 16. https://doi.org/10.1016/S2666-5247(22)00384-6Mykytyn AZ, Rosu ME, Kok A, et al. Antigenic mapping of emerging SARS-CoV-2 omicron variants BM.1.1.1, BQ.1.1, and XBB.1. Lancet Microbe 2023; published online Jan 16. https://doi.org/10.1016/S2666-5247(22)00384-6—In this Correspondence, the second sentence of the fourth paragraph should have read “Despite the antigenic similarities between BA.5 and BQ.1.1, thus far there is little evidence for increased neutralisation of BQ.1.1 by BA.5 bivalent vaccines, potentially due to immunological imprinting.” There has also been a correction to the appendix. Full-Text PDF Open Access